Psorospermin is one of the active constituents among cytotoxic xanthones derived from Psorospermum febrifugum extracts. This extract has been shown to exhibit cytotoxic and in vivo antitumor activity in the P388 mouse leukemia assay.
Psorospermin has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers; (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R), which are diastereomers. The psorospermin natural product is the 2′R, 3′R enantiomer.
In addition, Cassady 1 (J. Org. Chem., 52:3, 342-347 (1987)) discloses a non-chiral route (±) to 2′R, 3′S 5-methoxy-psorospermin. That is, this reference discloses a process for making a mixture of 2′R, 3′S and 2′S, 3′R without separating these components. Additionally, this reference is directed to making only the 5-methoxy (5-OMe) compound. Because Cassady 1 only discloses the 5-OMe derivative, the process disclosed in that document could be used with a variety of reducing agents, such as LiAlH4 (LAH), for the reduction of the unsaturated ester to the allylic alcohol. As many substituents are susceptible to LAH reduction, it would be useful to develop a process that overcomes this disadvantage. Cassady 1 also discloses a Wittig reaction to make an E (trans) olefin. It would be advantageous to selectively produce cis olefins and ultimately stereoselectively prepare enantiomers of psorospermin as is achieved through the process of the invention.
Cassady 2 (Tetrahedron Lett., 28, 27, 3075-3078 (1987)) disclosed the preparation of a substituted phenol having a Z (cis) olefin and used a Sharpless epoxidation to prepare a chiral epoxide, however, psorospermin or analogs thereof were not synthesized.
It would be useful to develop a process for making psorospermin that would overcome these disadvantages mentioned above as achieved by the method of the present invention.